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Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms.

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dc.contributor.authorColler, J.
dc.contributor.authorSomogyi, A.
dc.contributor.authorBochner, F.
dc.date.issued1999
dc.description.abstract<h4>Aims</h4>To compare the oxidative metabolism of (S)-mephenytoin and proguanil in vitro and to determine the involvement of various cytochrome P450 isoforms.<h4>Methods</h4>The kinetics of the formation of 4'-hydroxymephenytoin and cycloguanil in human liver microsomes from 10 liver samples were determined, and inhibition of formation was studied using specific chemical inhibitors and monoclonal antibodies directed towards specific CYP450 isoforms. Expressed CYP450 enzymes were used to characterize further CYP isoform contribution in vitro. Livers were genotyped for CYP2C19 using PCR amplification of genomic DNA followed by restriction endonuclease digestion.<h4>Results</h4>All livers were wildtype with respect to CYP2C19, except HLS#5 whose genotype was CYP2C19*1/CYP2C19*2. The Km, Vmax and CLint values for the formation of 4'-hydroxymephenytoin from (S)-mephenytoin and the formation of cycloguanil from proguanil ranged from 50.8 to 51.6 and 43-380 microm, 1.0-13.9 and 0.5-2.5 nmol mg-1 h-1, and 20.2-273.8 and 2.7-38.9 microl h-1 mg-1, respectively. There was a significant association between the Vmax values of cycloguanil and 4'-hydroxymephenytoin formation (rs=0.95, P=0.0004). Cycloguanil formation was inhibited significantly by omeprazole (CYP2C19/3A), troleandomycin (CYP3A), diethyldithiocarbamate (CYP2E1/3A), furafylline (CYP1A2), and (S)-mephenytoin. 4'-Hydroxymephenytoin formation was inhibited significantly by omeprazole, diethyldithiocarbamate, proguanil, furafylline, diazepam, troleandomycin, and sulphaphenazole (CYP2C9). Human CYP2E1 and CYP3A4 monoclonal antibodies did not inhibit the formation of cycloguanil or 4'-hydroxymephenytoin, and cycloguanil was formed by expressed CYP3A4 and CYP2C19 supersomes. However, only expressed CYP2C19 and CYP2C19 supersomes formed 4'-hydroxymephenytoin.<h4>Conclusions</h4>The oxidative metabolism of (S)-mephenytoin and proguanil in vitro is catalysed by CYPs 2C19 and 1A2, with the significant association between Vmax values suggesting that the predominant enzymes involved in both reactions are similar. However the degree of selectively of both drugs for CYP isoforms needs further investigation, particularly the involvement of CYP3A4 in the metabolism of proguanil. We assert that proguanil may not be a suitable alternative to (S)-mephenytoin as a probe drug for the CYP2C19 genetic polymorphism.
dc.identifier.citationBritish Journal of Clinical Pharmacology, 1999; 48(2):158-167
dc.identifier.doi10.1046/j.1365-2125.1999.00005.x
dc.identifier.issn0306-5251
dc.identifier.issn1365-2125
dc.identifier.orcidColler, J. [0000-0002-8273-5048]
dc.identifier.orcidSomogyi, A. [0000-0003-4779-0380]
dc.identifier.urihttp://hdl.handle.net/2440/14325
dc.language.isoen
dc.publisherBLACKWELL SCIENCE LTD
dc.source.urihttps://doi.org/10.1046/j.1365-2125.1999.00005.x
dc.subjectMicrosomes, Liver
dc.subjectHumans
dc.subjectMephenytoin
dc.subjectTriazines
dc.subjectCytochrome P-450 Enzyme System
dc.subjectIsoenzymes
dc.subjectAnticonvulsants
dc.subjectAntibodies, Monoclonal
dc.subjectAntimetabolites
dc.subjectEnzyme Inhibitors
dc.subjectFolic Acid Antagonists
dc.subjectOxidation-Reduction
dc.subjectGenotype
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectProguanil
dc.subjectIn Vitro Techniques
dc.titleComparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms.
dc.typeJournal article
pubs.publication-statusPublished

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